The mission of the National Biomedical Computation Resource (NBCR) is to conduct, catalyze, and enable biomedical research by harnessing forefront information technologies to advance mechanistic understanding in multi-scale biomedical problems that integrate diverse structural and functional measurements and span scales of biological organization from molecule to organ system. A central theme of NBCR has been the development and deployment of tools and infrastructure that enable biomedical problems to be addressed using mechanistic, structure- and physics-driven computational models that span scales of biological organization from atomistic simulations of molecular dynamics to continuum simulations of organ physiology and pathophysiology. We have been developing new modeling methods and tools that fill gaps in our ability to bridge critical mesoscales such as the macromolecular (nm) to subcellular (pm) levels. Excellent progress has been made building structurally detailed 3-D models of subcellular architecture from electron tomographic image volumes and using these to simulate transport and signaling processes. But to span from molecular to whole cell, tissue and organ scales other approaches will also be needed. The present supplementary revision application proposes to develop new multi-scale modeling tools and methods that: (1) Allow Markov models (MM) of molecular states to be defined using molecular simulations including molecular dynamics (MD), and Brownian dynamics (BD) models; (2) Facilitate the inclusion of Markov models into systems models of cell signaling, electrophysiology and mechanics suitable for use in multiscale models of cell, tissue and organ biomechanics and biophysics. The goal of this competitive revision application is to develop new multiscale modeling tools and methods that will help bridge the gap between molecular models of individual sarcomeric protein components including actin, myosin and components of the troponin-tropomyosin regulatory complex and cellular models of whole sarcomere activation and mechanics in striated muscle. We also identify other applications ofthe proposed new tools including studies on the role of sarcomeric mutations in muscle diseases and on the function of protein kinase A.